期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 14, 期 22, 页码 7434-7445出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2006.07.024
关键词
antiprotozoal agents; diamidines; minor-groove binde; prodrugs
资金
- NIAID NIH HHS [AI46365] Funding Source: Medline
- NIGMS NIH HHS [GM61587] Funding Source: Medline
A series of naphthalene analogues of highly active benzimidazole diamidines were synthesized using sequential Stille and Suzuki coupling reactions for preparation of the bis-nitrile intermediates. All of the diamidines showed strong DNA affinities as judged by high Delta T-m values with poly(dA-dT). The dicationic compounds were quite active in vitro versus Trypanosoma brucei rhodesiense (T. b. r.) exhibiting IC50 values ranging from 4 to 98 nM. These compounds were also active versus Plasmodium falciparum (P. f) giving IC50 values ranging from 4 to 33 nM. Two of the compounds showed good activity in vivo in the STIB900 model for acute African trypanosomiasis; one gave 3/4 cures and the other gave 4/4 cures on ip dosage of 20 mg/kg for 4 days. The amidoxime prodrugs of the naphthalene analogues were essentially ineffective. (c) 2006 Elsevier Ltd. All rights reserved.
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